Background:On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study.Methods:A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m−2 and was increased up to 120 mg m−2 according to the accelerated titration method and modified Fibonacci method.Results:One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m−2 of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m−2, which led to the conclusion that the maximum tolerated dose was 120 mg m−2, and the recommended dose was 90 mg m−2, although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration–time curve of ultrafilterable platinum at 120 mg m−2 NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin.Conclusion:The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004.

We demonstrate for the first time the formation of a fluid lipid bilayer membrane on mesoporous silicon substrates for bioapplications. Using fluorescence recovery after photobleaching, the diffusion coefficients for the bilayers supported on oxidized, amino-, and biotin-functionalized mesoporous silicon were determined. The biodetection of a single human umbilical vein endothelial cell was accomplished using confocal microscopy and exploiting Foerster resonance energy transfer effects after the incorporation of RGD covalently linked lipid soluble dyes, with fluorescence donor and acceptor components, within the fluid membrane. A signal response of greater than 100% was achieved via the clustering of RGD peptides binding with areas of high integrin density on the surface of a single cell. These results are a testament to the usefulness of such functional molecular assemblies, based on mobile receptors, mimicking the cell membrane in the development of a new generation of biosensors.

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Liposomes carrying both recombinant glycoprotein Ia/IIa (rGPIa/IIa) and Ib␣ (rGPIb␣) (rGPIa/IIa-Ib␣-liposomes) instantaneously and irreversibly adhered to the collagen surface in the presence of soluble von Willebrand factor (VWF) at high shear rates, in marked contrast with translocation of liposomes carrying rGPIb␣ alone on the VWF surface. In the absence of soluble VWF, the adhesion of rGPIa/IIa-Ib␣-liposomes to the collagen surface decreased with increasing shear rates, similar to liposomes carrying rGPIa/ IIa alone. While adhesion of liposomes with exofacial rGPIa/IIa and rGPIb␣ densities of 2.17 ؋ 10 3 and 1.00 ؋ 10 4 molecules per particle, respectively, was efficient at high shear rates, reduction in rGPIb␣ density to 5.27 ؋ 10 3 molecules per particle resulted in decreased adhesion even in the presence of soluble VWF. A 50% reduction in the exofacial rGPIa/IIa density resulted in a marked decrease in the adhesive ability of the liposomes at all shear rates tested. The inhibitory effect of antibody against GPIb␣ (GUR83-35) on liposome adhesion was greater at higher shear rates. Further, the anti-GPIa antibody (Gi9) inhibited liposome adhesion more than GUR83-35 at all shear rates tested. These results suggest that the rGPIa/IIa-collagen interaction dominates the adhesion of rGPIa/IIa-Ib␣-liposomes to the collagen surface at low shear rates, while the rGPIa/IIa-collagen and rGPIb␣-VWF interaction complements each other, and they synergistically provide the needed functional integration required for liposome adhesion at high shear rates. This study thus has confirmed for the first time the proposed mechanisms of platelet adhesion to the collagen surface under flow conditions using the liposome system. IntroductionThe basic and important platelet functions for primary hemostasis are adhesion and aggregation, and this can be easily understood from the observations that patients with congenital platelet membrane defects such as Bernard-Soulier syndrome or Glanzmann thrombasthenia are deficient in platelet adhesion or aggregation and have severe bleeding tendencies. The contribution of specific platelet receptors or adhesive proteins to platelet adhesion and aggregation onto immobilized collagen under flow conditions is usually studied with monoclonal antibodies or inhibitors specific to particular platelet receptors or adhesive proteins or, also, with blood from patients with congenital bleeding disorders deficient in specific receptors or adhesive proteins. These analyses indicate that initial platelet adhesion depends on the interaction of glycoprotein (GP) Ib/IX/V complexes on platelets with von Willebrand factor (VWF) adsorbed on the collagen surface. This is a rapid but low-affinity interaction, suggesting that it serves to tether platelets, flowing at high speed in the bloodstream, to the collagen surface. [1][2][3][4] The collagen receptors of the tethered platelets then bind strongly with the collagen surface, activating platelets to form aggregates. This was supported by observations that platelets ...